Development of heterocyclic-based frameworks as potential scaffold of 5-HT1A receptor agonist and future perspectives: A review

As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.


Introduction
[3] Serotonin (5-hydroxytryptamine, 5-HT), commonly referred to as 5-HT, represents a crucial neurotransmitter that modulates central nervous system activity and peripheral functions through interactions with 5-HT receptors. [4]Decreased serotonin levels in the synaptic gap are closely associated with the onset of depression and can lead to severe mood disorders. [5]Among the 7 different subtypes of 5-HT receptors (5-HT 1 -5-HT 7 ), [6][7][8][9][10] 5-HT 1A receptor has been extensively and intensively studied. [11][14] A key challenge in antidepressant research is the identification of compounds that target particular region(s) of the brain involved in rapid antidepressant action to specifically activate their 5-HT 1A receptors, while minimizing possible side effects that can arise through the activation of 5-HT 1A receptor subpopulations in other areas of the brain.Current data suggest that biased agonists targeting 5-HT 1A receptors hold promise as therapeutic compounds involving the 5serotonin mechanisms as antidepressant candidates. [15]n 5-HT 1A receptor ligand design, the heterocyclic scaffold is the most common in the molecule enhances the antidepressant activity of the compound, especially 5-HT 1A receptor agonist. [16,17]This review will focus on the medicinal chemistry work that allowed potent and selective 5-HT 1A R ligands to be identified.In particular, the structure-activity relationships of 5-HT 1A R ligands represented by piperazine, piperidine, benzothiazole, and pyrroloctone, specifying the pharmacological models and ligand binding modes of 5-HT 1A R antagonists and agonists (Fig. 1).

Piperazine
The piperazine with alkyl chain, a common scaffold in most CNS and neurological disorders compounds with neuroprotective and antidepressant activity, [18][19][20][21] is an important group for 5-HT 1A agonists.Comprehensive analysis of existing 5-HT 1A agonist and antidepression compounds, the piperazine with alkyl chain scaffold present a bridge between 2 heteroaromatic scaffold and where these molecular binding conformations in the 5-HT 1A .[24][25] Also, piperazines offer a wide range of opportunities to modify and to prove activity and pharmacokinetic profiles.Zareba et al [26] prepared various Fananserin derivatives and evaluated their antidepressant potential.SAR studies showed that increasing the length of the alkyl chain and substituting the 2nd/3rd position of the aryl piperazine with fluorine enhanced ligand affinity to the 5-HT 1A receptor.Molecular docking analysis further revealed the formation of hydrogen bonds between the carboxyl group of Asp106 (salt bridge 3.0-3.1 Å) and the nitrogen in the arylpiperazine ring, thus increasing the ligand binding stability to the 5-HT 1A receptor (Figs. 2-4).

Piperidine
The 6-membered heterocyclic structure of piperidine is commonly found in different naturally occurring bioactive compounds, [27] and studies have revealed its antidepressant potential, along with that of its derivatives. [28]In this context, after synthesizing various 5-aryl-4,5dihydrotetrazolo[1,5-a] thieno[2,3-e]pyridine derivatives that contained tetrazole along with heterocyclic substituents, Wang et al [29] tested their antidepressant-like activity in vivo through TST and FST performed on Kunming mice.In addition to identifying compound 10 (Fig. 5) as having the greatest potency, the results of TST and FST also showed that, at a dose of 40 mg/kg, this compound could achieve a 43.73% and 55.33% reduction in immobility, respectively.Compound 10 or fluoxetine (control) was then administered to the mice before determining the serum level of 5-HT in their brains using enzyme-linked immunosorbent assay (ELISA).In this case, mice from the experimental group had higher amounts of serum 5-HT in their brains compared with those from the fluoxetine group.SAR studies further revealed improved activity and potency when the para-position of the aromatic ring, attached to the piperidine ring's 4th position, possessed electron-absorbing groups.In a different study, following the synthesis of different alkoxypiperidine derivatives, Wang et al [30] assessed their potential to bind to 5-HT 1A receptors as well as to inhibit 5-HT's reuptake.Of all derivatives, the highest antidepressant activity, assessed through TST, was observed at a dose of 40 mg/kg for compounds 11 and 12 (Fig. 5), with these compounds even showing potent antagonism to 5-HT 1A (Ki values: 12 and 17 nM, respectively) as well as moderate 5-HT reuptake inhibition (RUI) (IC 50 values: 177 and 85 nM, respectively).In vitro studies further suggested that 5-HT 1A receptors' activity was linked to the length of the linkage bond.Therefore, out of various derivatives, compound 10 was identified as the lead compound due to its dose-dependent reduction in the immobility time of mice, as demonstrated through FST and TST, its high potential to inhibit serotonin reuptake (IC 50 value of 14 nM) and its high affinity for 5-HT 1A receptors (Ki value of 12 nM).In addition, animal testing demonstrated good potency and metabolic stability of the compound, while replacing piperazine with piperidine further inhibited serotonin reuptake binding by 5-HT 1A . [31]Different piperidine and piperazine substituted piperamide congeners were synthesized by Prashanth et al [32] based on the compound's chemical structure.Although most compounds (at 20 mg/kg) exhibited antidepressant activity during TST and FST, the greatest potency was observed in the case of compounds 13 and 14 (Fig. 5) for which the immobility time decreased by 78.18 and 76.18 seconds, respectively during TST as well as 32.15 and 30.8 seconds, respectively, during FST in comparison with the control.SAR studies have shown that the piperidine moiety is essential for pharmacological activity, with superior antidepressant effects observed when the hydroxyl group occurs at the 4th position of the piperidine ring as opposed to the 3rd position.Different studies have reported the antidepressant effects of 3-[5-(aryl [1,3,4]oxadiazole-2-yl]-piperidine derivatives.In this context, FST results have shown that, in comparison with standard drugs such as tiagabine (10 mg/kg) and imipramine (50 mg/kg) or even a control, 10 mg/kg of compounds 16 to 18 (Fig. 5) could induce a significant reduction in immobility time.This effect was particularly obvious for compound 18, identified as the most potent, with the immobility time reduced to 103 seconds as opposed to 180 seconds in the case of the control.In contrast, no effects were observed for test compounds in 5-HTP induced head twitches. [33]In order to improve the antidepressant activity of arylalkyl piperazine derivatives, synthesized various arylalkyl piperidine derivatives were prepared by Zheng et al [34] prior to their screening as triple uptake inhibitors.Compared to the positive drug venlafaxine, lower immobility times were noted for compounds 19 and 20 (Fig. 5) in the dose range of 10 to 50 mg/kg during TST.SAR studies further showed greater inhibition of 5-HT, NA, and DA transporters for benzothiophene and 3,4-dichlorobenzene on the aromatic ring attached to the first position of the piperidine ring.

Benzothiazole
The nucleus of a benzothiazole heterocycle consists of a fused benzene and thiazole motif, with sulfur and nitrogen incorporated within this structure. [35]Benzothiazole derivatives are of significance in CNS-related drugs, such as antidepressants. [36]39] In view of enhancing the efficacy of potential antidepressant compounds, different benzoxazole/benzothiazole derivatives containing 2,3-dihydrobenzo[b} [1,4]dioxine were synthesized by Wang et al [37] before assessing their ability to bind 5-HT 1A receptors based on FST and TST assays.Overall, most compounds exhibited binding activity towards 5-HT 1A as well as antidepressant effects, with compound 21 (Fig. 6), in particular, displaying the greatest activity.Indeed, with a Ki value of 31 nM, this compound not only displayed optimal binding to 5-HT 1A receptors at a dose of 40 mg/kg but also induced a significant reduction in the immobility time of mice.Furthermore, the ED 50 value of compound 21 in FST compared to the control drug promethazine was found to be 39 mg/kg during a dose-effect relationship study.The results of a SAR study further showed that the activity of compound 21 on 5-HT 1A receptors increased as the length of the linkage bond increased from 3 to 4 carbons.Two benzothiazole-based derivatives 22 and 23 (Fig. 6) showed dual binding ability to both SERT and 5HT 1A receptor sites.In a different study piperazine was replaced by piperidine in the structure of benzothiazole derivatives, with subsequent SAR analysis indicating reduced binding intensity of 5-HT 1A receptors by 2-fold but a 64 nM increase at the SERT site after such structural modifications in compound 23. [38]To identify fast-acting antidepressant compounds, various benzothiazole derivatives targeting 5-HT 1A receptors were also prepared by Demir Özkay et al [39] before orally administering 40 mg/kg of these compounds to mice at 1, 5, and 24 hours prior to TST and MFST.The results indicated that the immobility time of mice decreased significantly for compounds 24 to 28 at the above dose (Fig. 6) compared with the control and standard drug fluoxetine (20 mg/kg).

Pyrrolidine
Pyrrolidine is a saturated 5-membered heterocycle compound containing a secondary amine. [40,41]Different 3-(1H-indol-3yl)pyrrolidine-2,5-dione derivatives were synthesized by Wrobel et al [42] prior to their screening to obtain agonist compounds with dual action on SERT and 5-HT 1A receptors.SAR studies have revealed the high potency of pyrrolidine-2,5-dionecontaining compounds for dual binding to SERT and 5-HT 1A receptors, with the piperidine ring having a stronger affinity for the 5-HT 1A receptor.In particular, compound 31 exhibited greater 5-HT 1A activity in comparison with a serotonin control (Ki value of 3.2 nM vs 2.1 nM).Additionally, in vivo binding assays showed that compounds 29 and 30 could also display binding activity towards receptors other than 5-HT 1A , thus highlighting their potential as multitargeted antidepressant compounds.Based on this, various 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were designed and prepared by the same group [43] before screening them for 5-HT 1A / D 2 receptor binding activity as well as 5-HT reuptake inhibition activity.Among them, compounds 33 and 34 (Fig. 7) exhibited binding activity to 5-HT 1A receptors, with higher affinity being especially observed for the former (Ki value: 0.4 nM).However, compound 34 also displayed multitargeting activity, binding to SERT transporters, D 2 receptors and 5-HT 1A (Ki values of 64, 182, and 1.3 nM, respectively).The SAR study further indicated that the o-substituted ligands of phenylpiperazine exhibited higher affinity for 5-HT 1A R, while the para-substituted compounds showed better affinity for the SERT transporter.Additional evaluation of the binding affinity of 3-(1H-indol-3-yl) pyrrolidine-2,5-dione derivatives for 5-HT 1A receptors as well as their inhibitory effects on serotonin reuptake revealed their high affinity for the receptor, with compounds 35 and 36 (Fig. 7) exhibiting the highest activity (Ki values of 2.3 and 3.2 nM, respectively).Compounds 37 and 38 (Fig. 7) also displayed dual binding towards 5-HT 1A /SERT with Ki values of 7.0 nM (5-HT 1A ) and 17.5 nM (SERT) for compound 37 as well as 4.9 nM (5-HT 1A ) and 17.5 nM (SERT) for compound 38 over 15 days.In vivo FST assays also identified the lead compound MW005 (30) as the most active due to its good binding ability to the 5-HT 1A receptor and strong antidepressant activity.Therefore compound 30 was identified as the lead compound.

Conclusion
In this review, we delve into the pivotal role of azacycles in the research and development of antidepressants.Through detailed structure-activity relationship studies, we provide consistent structural characteristic information for the activity of these preclinical molecules.Notably, the piperazine scaffold has emerged as a key platform for antidepressant drug development due to its superior chemical reactivity and CNS pharmacodynamics.
This review highlights the following points: the tunable nature of the piperazine structure, typically consisting of a 3 to 4 carbon chain linking 2 aromatic rings, one of which is attached to the piperazine moiety; the crucial chemical features, including halogen substitution on 1 aromatic ring and hydrogen bond acceptors on the other, which enhance interactions with biological targets.Additionally, we emphasize the significance of other nitrogen-containing heterocycles as ligands for the 5-HT 1A R.These compounds do not merely bind to 5-HT 1A R; most of them selectively act on multiple serotonin receptors, thereby exhibiting antidepressant effects.
5-HT 1A receptor ligands offer several advantages in antidepressants and neuropsychiatric drugs compared to existing antidepressants.These advantages primarily manifest in the following aspects: multi-target mechanisms: 5-HT 1A receptor ligands can bind not only to 5-HT 1A receptors but also to various other receptors, such as 5-HT 2A , 5-HT 2C , and 5-HT 7 , resulting in multi-target mechanisms.This may contribute to improved efficacy, reduced side effects, and decreased resistance; antianxiety effect: 5-HT 1A receptor ligands exhibit strong antianxiety effects, likely due to their agonistic action on 5-HT 1A receptors.They may be more suitable for treating patients with depression accompanied by anxiety symptoms compared to existing antidepressants; rapid onset: 5-HT 1A receptor ligands demonstrate rapid onset, likely due to their direct agonistic effect on 5-HT 1A receptors.They may be more suitable for treating acute depressive episodes compared to existing antidepressants such as selective serotonin reuptake inhibitors (SSRIs); fewer side effects: 5-HT 1A receptor ligands tend to have fewer side effects such as sexual dysfunction and weight gain during treatment.This may be attributed to their multi-target mechanisms and regulatory effects on other receptors; less drugdrug interactions: 5-HT 1A receptor ligands exhibit fewer interactions with other drugs, potentially improving patient compliance and safety.However, it should be noted that while 5-HT 1A receptor ligands offer advantages in antidepressants and neuropsychiatric drugs, more clinical studies are needed to confirm their efficacy and safety.Furthermore, they still face challenges in practical applications, such as drug dosage, administration routes, and individual differences.Therefore, further research and exploration are necessary before applying 5-HT 1A receptor ligands in clinical treatment.Finally, this review focuses on the latest reported compounds with 5-HT 1A R binding activity, providing guidance for researchers in designing and developing novel nitrogen-containing heterocyclic antidepressants.The aim is to discover drug candidates with stronger binding affinity, higher activity, and lower side effects.Looking ahead, these findings have the potential to not only promote the development of antidepressants but also open new avenues for treating related mental illnesses.Medicine WY and YM contributed equally to this work.This work was supported by the Natural Science Foundation of Anhui Province (No. 2208085MH272), the Natural Science Research Project of Anhui EducationalCommittee (Nos.2023AH050800, KJ2020A0423 and KJ2020A0376).